The role in promotion of transformation of cell surface glycolipids, particularly gangliosides is being studied. Phorbol esters produce specific ganglioside changes under conditions in which they regulate differentiation; binding to specific surface gangliosides is required for the function of certain hormones and toxins which regulate growth and differentiation. Tumor-promoting but, not nonpromoting, phorbol esters produce specific changes in ganglioside synthesis, principally a 10-fold decrease in the synthesis of a trisialoganglioside (GT). This change is blocked by antipromoting concentrations of retinoic acid. Variants of JB6 mouse epidermal cells, which are promotable to tumor cell phenotype by phorbol esters, show the GT decrease while their nonpromotable counterparts do not, suggesting that a ganglioside shift may play a causal role in promotion of tranformation. This suggestion has been further substantiated by the observation that reconstitution of JB6 cells with GT, but not with other sialic acid-containing glycoconjugates, blocks promotion of transformation by 12-0-tetradecanoylphorbol-13-acetate (TPA). Current efforts are directed to selecting JB6 cells for resistance to the GT response to TPA and asking whether they have been coselected for resistance to promotion of transformation.